Throughout this disclosure, various publications are referenced by a number within parenthesis. The full bibliographic citation for each reference can be found at the end of this application, immediately preceding the claims. The disclosures of these references are hereby incorporated by reference into this disclosure to more fully describe the state of the art to which this invention pertains.
Most of the cytotoxic drugs used in cancer chemotherapy have a narrow chemotherapeutic utility and serious side effects at high dosages. As a result, drug delivery systems have been developed to modify the biodistribution of cytotoxic drugs, improving their selectivity for tumors or reducing the damage to normal tissues. Liposomes have been used extensively in this regard. The use of liposomes as a drug delivery system has provided a means to improve the therapeutic utility of some conventional drugs [7, 19]. Since many liposomes are rapidly taken up by the cells of the mononuclear phagocyte system or reticuloendothelial system (RES) [12, 20], they have been effective in delivering drugs to organs of the RES. However, their rapid clearance from the bloodstream has also limited their utility for transporting drugs to disease sites beside the RES.
Recently prolongation of the circulation of liposomes in blood and reduction of its uptake by RES have been achieved when the liposomes are stabilized by a polyethylene glycol head group [12, 21]. The increased circulation titers have made possible enhanced antitumor activity [7]. Another approach has been to modify the liposomes to attain active targeting to tumor cells by conjugating the liposomes with antibodies specific for tumor cells [11,22]. One potential problem with antibody-coated liposomes is that they may be more immunogenic, resulting in shorter circulatory half-life, obviously multiple considerations need to be made in designing liposomes as a drug delivery system.
Accordingly, a need exists to provide compositions and methods for tissuespecific delivery of drugs and in particular, for drugs specific for malignant liver tissue. This invention satisfies these needs and provides related advantages as well.